Although most leukemias and lymphomas respond to conventional and high dose therapy, only a small fraction of adults with these diseases are cured. Since most of these tumors can be induced into a complete remission, the major impediment to their cure is the persistence of resistant, minimal residual disease. Over the last decade, the members of this Program have investigated oncogenes, growth regulation, surface molecules, and set up animal models and attempted to address this issue by administering increasingly intensified treatments with only modest improvement in outcome, yet these approaches have been complicated by severe toxicities including myelodysplasia. Although we have translated our basic laboratory studies to the clinic by purging tumor cells from autologous marrow, detecting minimal residual disease, and administering immunotoxins as primary therapy and agents to treat minimal residual disease, most of our patients still relapse. Therefore, to address these issues, we have joined together in a PROGRAM PROJECT to develop novel, non-overlapping treatment strategies which can be added to present treatment approaches in the hope of eradicating residual resistant disease. We believe that the generation of leukemia/lymphoma therapies will continue to come from laboratory studies aimed at understanding the pathogenesis and the molecular and biological characteristics of these diseases. To achieve our goals, we have assembled a team of basic scientists, immunologists, clinical scientists, and oncologists who bring to the Program expertise in a wide range of areas. The central hypothesis of this Program Project is to determine how tumor cells evade the immune system, cytotoxic therapy, and immunotherapies. To this end, we plan to study how these neoplastic cells grow; how they interact with the immune system, why the immune system fails to recognize and reject most human leukemias and lymphomas; how to detect minimal residual disease; how to optimally use autologous bone marrow transplantation without damaging hematopoietic stem cells, ad how to harness the immune system to develop novel immunotherapies. We expect these studies to demonstrate specific defects in antigen presentation, antigen recognition, and T cell responses. Our therapeutic objectives will be to attempt to repair one or more of the defective components of the immune system by gene transfer, cytokine therapy, and cell based immunotherapies. By translating basic laboratory studies to the clinic, we hope both improve outcome and decrease toxicity for patients who suffer with these dreaded diseases.